In the physiological state, the synthesis of connective tissue is in dynamic equilibrium with the degradation of the extracellular matrix. That degradation is due to zinc proteases (metalloproteases) secreted by the cells of the existing matrix: those proteases are, without implying any limitation, collagenases (MMP-1, MMP-8, MMP-13) or gelatinases (MMP-2, MMP-9), Matrilysin (MMP-7) and stromelysins (MMP-3, MMP-10, MMP-11).
In the normal state, those catabolic enzymes are regulated in their synthesis and in their secretion as well as in their extracellular enzymatic activity by natural inhibitors, such as xcex12-macroglobulin or TIMPs (Tissue Inhibitors of MetalloProteinase), which form inactive complexes with the metalloproteases.
A factor common to the pathologies in which those enzymes are implicated is an imbalance between the activity of the activated enzymes and the activity of their natural inhibitors, the consequence of which is excessive tissue degradation.
Uncontrolled and accelerated degradation of tissue by way of resorption of the extracellular matrix catalysed by the metalloproteases is a parameter common to a number of pathological conditions, such as rheumatoid arthritis, arthrosis, tumour invasion and growth, including malignant dissemination and the formation of metastases, ulceration, atherosclerosis, etc.
More recently, it has been demonstrated that each of those pathologies may be associated with the dominant activity of one or more metalloproteases. Thus, experiments carried out on the Wistar rat have shown a relationship between the development of osteoarthritis and an increase in the production of stromelysin (MMP-3) (Pathol. Res. Pract. 1998, 194, 41). On the other hand, it has been possible to correlate the appearance of rheumatoid arthritis with an increased expression of certain collagenases (MMP-8), which are responsible, alongside polymorphonuclear neutrophils, for cartilage degradation (J. Biol. Chem., 1997, 272, 31504). As for the gelatinases, they seem to play a significant role in tumour invasion. Indeed elevated levels of those enzymes have been demonstrated, in vivo, in several types of tumour, and an activation phenomenon in cancer cells confers invasive properties to non-metastatic tissues (J. of Immunology, 1998, 160, 2967).
Recently, BB94, a metalloprotease inhibitor, has exhibited anti-tumour activity in clinical use, where it has proved to be active in ovarian cancers (Becket et al., DDT 1996, 1, 16).
It may therefore be expected that a metalloprotease inhibitor will restore the equilibrium between protease and inhibitor and, as a result, favourably modify the development of those pathologies. Selectivity in respect of one of the different types of enzyme would allow the efficacy of such a compound to be increased.
Metalloprotease inhibitors are also capable of inhibiting the release of TNF-xcex1 (Tumour Necrosis Factor-xcex1) from cells. TNF-xcex1 is a powerful inflammation mediator implicated in numerous inflammatory pathologies, such as rheumatoid arthritis, asthma etc.
The concept of compounds capable of opposing the release of TNF-xcex1 is hence of interest especially in the treatment of the pathologies mentioned above.
A certain number of metalloprotease inhibitors have been described in the literature, especially the compounds described in Patent Specifications WO 97/24117, WO 96/35711 and EP 803 505.
The compounds of the present invention are not only new but have also proved to be more powerful inhibitors of metalloproteases and/or of TNF-xcex1 release than the inhibitors described in the literature, thus making them potentially useful in the treatment of cancers, rheumatic diseases, such as arthrosis and rheumatoid arthritis, ulcers, atherosclerosis, asthma etc.
The present invention relates to the compounds of formula (I): 
wherein:
n is 0 or 1,
R1, R2, R3 and R4 independently represent a hydrogen atom or an alkyl group, or R1 and R3 form together with the carbon atoms carrying them a (C5-C8)cycloalkyl group and in that case R2 and R4 each represents a hydrogen atom,
R5 represents a hydrogen atom, an alkyl, (C3-C8)cycloalkyl, cycloalkyl-(C3-C8)alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkylalkyl group, or a xe2x80x94COxe2x80x94R6 group,
R6 represents a group R7, OR7 or NR7R8 wherein R7 represents an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, and R8 represents an alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl or optionally substituted heterocycloalkylalkyl group, or,
R5 and R6 form together with the nitrogen atom and the group Z carrying them a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic group having from 5 to 16 ring members and containing from 1 to 7 hetero atoms selected from nitrogen, oxygen and sulphur and/or a sulphoxide or sulphone group, the said cyclic group being optionally substituted by from 1 to 7 identical or different substituents selected from halogen, alkyl, amino, hydroxy, alkoxy, nitro, mercapto, alkylthio, cyano, oxo, imino, thioxo, carboxy, alkoxycarbonyl and aminocarbonyl (optionally substituted on the nitrogen atom by one or two alkyl groups),
R10 represents a hydrogen atom or a hydroxy group, and in the latter case R1, R2, R3 and R4 are independently selected from hydrogen and alkyl,
Z represents a xe2x80x94COxe2x80x94 group or a xe2x80x94SO2xe2x80x94 group,
Y represents a hydroxy, alkoxy, alkenyloxy or benzyloxy group or an xe2x80x94NHxe2x80x94OR group wherein R represents a hydrogen atom or an alkyl, alkenyl or benzyl group,
X represents: a sulphur atom or a xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 group and in those cases R3 and R4 are other than an alkyl group, or X represents a xe2x80x94COOxe2x80x94 group and in that case R1 and R3 together form a (C5-C8)cycloalkyl group, or X represents an oxygen atom,
W represents a W1xe2x80x94(A)p group or a W1xe2x80x94Bxe2x80x94W2xe2x80x94(A)p group wherein W1 and W2 independently represent an aryl or heteroaryl group, A, a substituent of the aromatic cyclic group, is attached at any of the positions of that cyclic group and represents a halogen atom or an alkyl, alkoxy, hydroxy, mercapto, cyano, amino, nitro, cyanoalkyl or thioalkyl group, B represents a bond, an oxygen atom or an alkylene, alkenylene or alkynylene group (wherein any one of the carbon atoms of the alkylene, alkenylene or alkynylene groups may be replaced by an oxygen atom), and p represents an integer of from 0 to 5 inclusive,
T1 and T2 independently represent a bond or an alkylene, alkenylene or alkynylene group,
wherein when T2 represents a bond and n is 0 and at the same time R1, R2, R3 and R4 each represents a hydrogen atom, then R5 and R6 form together with the nitrogen atom and the group Z carrying them a bicyclic group as defined hereinbefore that is other than a 1,3-dioxo-2,3-dihydro-1H-2-isoindolyl group, a 2,5-pyrrolidinedione group or an optionally substituted 2,5-dioxo-1-imidazolinyl group,
to their enantiomers, diastereoisomers, and also addition salts thereof with a pharmaceutically acceptable acid or base.
In the compounds of formula (I)
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms,
the term xe2x80x9calkenylxe2x80x9d denotes a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms and containing from 1 to 3 double bonds,
the term xe2x80x9calkylenexe2x80x9d denotes a linear or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms,
the term xe2x80x9calkenylenexe2x80x9d denotes a linear or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms and containing from 1 to 3 double bonds,
the term xe2x80x9calkynylenexe2x80x9d denotes a linear or branched divalent hydrocarbon radical having from 1 to 6 carbon atoms and containing from 1 to 3 triple bonds,
the term xe2x80x9calkoxyxe2x80x9d denotes a linear or branched alkoxy group having from 1 to 6 carbon atoms,
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group,
the term xe2x80x9cheteroarylxe2x80x9d denotes an aromatic or partially aromatic mono- or bi-cyclic group having from 5 to 11 ring members and containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur, for example a furyl, pyridyl, thienyl, indolyl, quinolyl . . . group,
the term xe2x80x9cheterocycloalkylxe2x80x9d denotes a mono- or bi-cyclic group having from 5 to 11 ring members and containing from 1 to 4 hetero atoms selected from nitrogen, oxygen and sulphur, it being possible for that group to contain one or more unsaturations without being of aromatic character,
the expression xe2x80x9coptionally substitutedxe2x80x9d applied to the terms aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl denotes that the cyclic moiety of those groups may be substituted by one or more halogen atoms or alkyl, alkoxy, hydroxy, mercapto, cyano, amino, nitro, cyanoalkyl, thioalkyl, aryloxy or arylalkoxy groups.
Among the pharmaceutically acceptable acids there may be mentioned hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid etc.
Among the pharmaceutically acceptable bases there may be mentioned sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of the invention are those wherein R10 represents a hydrogen atom.
Other preferred compounds of the invention are those wherein R10 represents a hydroxy group.
Advantageously, in the compounds of formula (I), X represents an oxygen or sulphur atom or a xe2x80x94SO2xe2x80x94 group.
Preferably, in the compounds of formula (I), R2 and R4 represent a hydrogen atom.
Preferred compounds of the invention are those wherein n is 0.
Other preferred compounds of the invention are those wherein n is 1.
Other preferred compounds of the invention are those wherein R1 and R3 form together with the carbon atoms carrying them a (C5-C8)cycloalkyl group and R2 and R4 each represents a hydrogen atom. More especially, R1 and R3 form a cyclopentane.
Other preferred compounds of the invention are those wherein R2 and R3 represent a hydrogen atom and R1 and R3 independently represent a hydrogen atom or an alkyl group.
Preferably, in the compounds of formula (I) R5 and R6 form with the nitrogen atom and the group Z carrying them a saturated, partially unsaturated or unsaturated mono- bi- or tri-cyclic group having from 5 to 16 ring members and containing from 1 to 7 hetero atoms selected from nitrogen, oxygen and sulphur and/or a sulphoxide or sulphone group, the said cyclic group being optionally substituted by from 1 to 7 identical or different substituents selected from halogen, alkyl, amino, hydroxy, mercapto, alkoxy, nitro, cyano, oxo, imino and thioxo. Among the substituents there may advantageously be mentioned the groups oxo, amino and alkyl, substituents of the oxo type numbering more especially 1 or 2. Specifically, there may be mentioned the groups 1,3-dioxo-2,3-dihydro-1H-2-isoindolyl, 4-amino-1,3-dioxo-2,3-dihydro-1H-2-isoindolyl, 5-amino -1,3-dioxo-2,3-dihydro -1H-2-isoindolyl, 1-oxo-2,3-dihydro-1H-2-isoindolyl, 2,4-dioxo-3,4-dihydro-2H-1,3-benzoxazin-3-yl, 5,5-dimethyl-2,4-dioxo-1,3-oxazolan-3-yl, 4,4-dimethyl-2,5-dioxo-1-imidazolidinyl, 2,4-dioxo-1,3-thiazolan-3-yl, 3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl, 1H-benzo[f]isoindole-1,3(2H)-dione, 1H-benzo[d,e]isoquinoline-1,3(2H)-dione, 5H-dibenzo[c,e]azepine-5,7(6H)-dione and, especially advantageously, the groups 1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-2-yl, 1,1,3-trioxo-2,3-dihydro-1H -1xcex6-benzo[d]isothiazol-2-yl, 1-oxo-1,2-dihydro-2-phthalazinyl, 4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl and 2,4-dioxo-1,2,3,4-tetrahydro-3-quinazolinyl.
In the compounds of formula (I), T1 and T2 are preferably independently selected from a bond and an alkyl group, T1 being more especially an alkyl group (for example methyl or ethyl).
Preferably, in the compounds of formula (I) Y represents a hydroxy group or an xe2x80x94NHxe2x80x94OR group, R preferably being a hydrogen atom.
Preferred groups W of the invention are the groups W1xe2x80x94(A)p and W1xe2x80x94Bxe2x80x94W2xe2x80x94(A)p wherein p is 1 and B represents a bond, W1 preferably being an aryl group and A advantageously being selected from halogen, alkoxy and cyano. The preferred aryl group of the invention is the phenyl group.
Among the heteroaryl groups there are mentioned more specifically the groups pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrimidinyl, . . .
A very advantageous aspect of the invention concerns the compounds of formula (I) wherein R2, R4 and R10 each represents a hydrogen atom, n is 0, T1 and T2 are independently selected from a bond and an alkylene group, W represents a W1xe2x80x94(A)p group or a W1xe2x80x94Bxe2x80x94W2xe2x80x94(A)p group wherein p is 1 and B represents a bond, R5 and R6 form together with the nitrogen atom and the group Z carrying them a saturated, partially unsaturated or unsaturated mono- or bi-cyclic group containing from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur and/or a sulphoxide or sulphone group, the said cyclic group being optionally substituted by from 1 to 7 identical or different substituents selected from halogen, alkyl, amino, hydroxy, alkoxy, nitro, cyano, oxo, imino and thioxo, and Y represents a hydroxy group or an xe2x80x94NHxe2x80x94OH group.
Among the latter there may be mentioned, more specifically, on the one hand those in which R1 and R3 form together with the carbon atoms carrying them a (C5-C8)cycloalkyl group, and on the other hand those wherein R1 and R3 each represents a hydrogen atom.
Among the preferred compounds of the invention there may be mentioned, more especially, the following compounds:
2-[(4-biphenyl)oxymethyl]-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyric acid
(1R,2S,5R)- and (1S,2R,5S)-2-[(4xe2x80x2-chloro-4-biphenyl)sulphanyl]-5-[(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)methyl]-1-cyclopentanecarboxylic acid
1R,2S,5R)- and (1S,2R,5S)-2-[2-(4xe2x80x2-fluoro-4-biphenyl)ethylsulphanyl]-5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-1-cyclopentanecarboxylic acid
2-[(4-biphenyl)oxymethyl]-4-(1,1,3-trioxo-2,3-dihydro-1H-1xcex6-benzo[d]isothiazol-2-yl)butyric acid
2-[(4xe2x80x2-chloro-4-biphenyl)oxymethyl]-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyric acid
2-[(4xe2x80x2-cyano-4-biphenyl)oxymethyl]-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyric acid
2-[(4xe2x80x2-chloro-4-biphenyl)sulphanylmethyl]-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyric acid
2-{[2-(4xe2x80x2-chloro-4-biphenyl)ethyl]sulphanylmethyl}-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyric acid
(1R,2S,5R)- and (1S,2R,5S)-2-[2-(4-bromophenyl)ethylsulphanyl]-5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-1-cyclopentanecarboxylic acid
(1R,2S,5R)- and (1S,2R,5S)-2-[2-(4xe2x80x2-chloro-4-biphenyl)ethylsulphanyl]-5-[(1,3-dioxo-2,3-dihydro-1H-2-isoindolyl)methyl]-1-cyclopentanecarboxylic acid
2-[2-(4xe2x80x2-chloro-4-biphenyl)ethoxymethyl]-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3yl)butyric acid
2-[(4-biphenyl)oxymethyl]-N-hydroxy-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyramide
(1R,2S,5R)- and (1S,2R,5S)-2-[(4xe2x80x2-chloro-4-biphenyl)sulphanyl]-N-hydroxy-5-[(4-oxo-3,4-dihydro -1,2,3-benzotriazin-3-yl)methyl]-1-cyclopentanecarboxamide
2-[(4-biphenyl)oxymethyl]-N-hydroxy-4-(1,1,3-trioxo-2,3-dihydro-1H-1xcex6-benzo[d]isothiazol-2-yl)butyramide
2-[(4xe2x80x2-chloro-4-biphenyl)oxymethyl]-N-hydroxy-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyramide
2-[(4xe2x80x2-cyano-4-biphenyl)oxymethyl]-N-hydroxy-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyramide
2-[(4xe2x80x2-chloro-4-biphenyl)sulphanylmethyl]-N-hydroxy-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyramide
2-{[2-(4xe2x80x2-chloro-4-biphenyl)ethyl]sulphanylmethyl}-N-hydroxy-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyramide
2-[2-(4xe2x80x2-chloro-4-biphenyl)ethoxymethyl]-N-hydroxy-4-(4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yl)butyric.
The present invention relates also to a process for the preparation of the compounds of formula (I).
The process for the preparation of the compounds of formula (I) wherein R10 represents a hydrogen atom and X represents a sulphur atom or a xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 group is characterised in that there is used as starting material a compound of formula (II/a) 
wherein R1, R2, R3 and R4 are as defined for formula (I), P represents an alkoxy, alkenyloxy or benzyloxy group and m is an integer 0 or 1, which may be subjected to a sequence of reactions conventional in organic chemistry, for the purpose of homologising the carbon chain carrying the hydroxy function, to yield a compound of formula (II/b): 
wherein R1, R2, R3, R4 and P are as defined hereinbefore, T1xe2x80x2, which is other than a bond or a methylene group, has the same meanings as T1 in formula (I), and Q represents a hydroxy group or an amino group according to the homologisation sequence used, the compounds of formulae (II/a) and (II/b) constituting the totality of the compounds of formula (II): 
wherein R1, R2, R3, R4, Q and P are as defined hereinbefore and T1 has the same meanings as for formula (I), which compounds are subjected, in basic medium, to the action of a compound of formula (III):
HSxe2x80x94T2xe2x80x94W1xe2x80x94(A)pxe2x80x83xe2x80x83(III)
wherein T2, W1, A and p are as defined for formula (I), to yield a compound of formula (IV/a): 
wherein R1, R2, R3, R4, T1, T2, W1, A, p and P are as defined hereinbefore, which, when one of the substituents A represents a halogen atom, may be treated
with bis(tributyltin), in the presence of a palladium catalyst, to yield the corresponding: stannyl compound, which is subjected under the same conditions to the action of a halogen compound Hal-W2xe2x80x94(A)p wherein W2, A and p are as defined for formula (I) and Hal represents a halogen atom,
or with an organometal compound such as a vinyl compound, a tin compound or a boronic acid compound, in the presence or absence of a palladium catalyst, to yield a compound of formula (IV/b): 
xe2x80x83wherein R1, R2, R3, R4, T1, T2, W1, A, p, P and Q are as defined hereinbefore and B and W2 are as defined for formula (I), the compounds of formulae (IV/a) and (IV/b) constituting the totality of the compounds of formula (IV): 
xe2x80x83wherein R1, R2, R3, T1, T2, Q, P and W are as defined hereinbefore, which compounds of formula (IV) are subjected:
either, when Q represents a hydroxy group, to a Mitsunobu-type reaction using as reagent a compound of formula (V): 
xe2x80x83wherein R5, R6, Z and n are as defined for formula (I),
or, after conversion of hydroxy into a leaving group, to the action, in basic medium, of a salt of the compound of formula (V) as defined hereinbefore,
or, when Q represents an amino group, to the action, in basic medium, of a compound of formula (VI): 
xe2x80x83wherein R5, R6 and Z are as defined for formula (I) and Alk represents a linear or branched (C1-C6)alkyl group, to yield a compound of formula (I/a): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, T1, T2, W, Z, P and n are as defined hereinbefore, the ester function of which may be hydrolysed in acid or basic medium to yield a compound of formula (I/b): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, T1, T2, W, Z and n are as defined hereinbefore, the carboxylic acid function of which may be converted into hydroxamate or into hydroxamic acid to yield a compound of formula (I/c): 
xe2x80x83wherein R1, R2, R3, R4, R5, R6, T1, T2, W, Z and n are as defined hereinbefore and R has the same meanings as for formula (I), which compounds of formulae (I/a), (I/b) and (I/c):
are optionally purified according to a conventional purification technique,
are optionally separated into their isomers according to a conventional separation technique,
and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base,
the sulphur atom of which may be oxidised to sulphone or to sulphoxide by conventional oxidation methods at any point during the synthesis, it being understood that the group P present in the various formulae described hereinbefore must be so chosen as to be resistant to the various reagents used and, with that purpose in mind, may be modified at any point during the synthesis, and that the order of the reactions used in the above process may be modified with the aim of simplifying the process or if there is incompatibility between certain reactions and the substituents present in the molecule.
The process for the preparation of the compounds of formula (I) wherein R10 represents a hydrogen atom and X represents an oxygen atom is characterised in that there is used as starting material a compound of formula (VII/a): 
wherein R1, R2, R3, R4, T2, W1, A and p are as defined for formula (I) and m is an integer 0 or 1, which may be subjected to a sequence of reactions conventional in organic chemistry, for the purpose of homologising the carbon chain carrying the hydroxy function, to yield a compound of formula (VII/b): 
wherein R1, R2, R3, R4, T2, W1, A and p are as defined hereinbefore, T1xe2x80x2, which is other than a bond or a methylene group, has the same meanings as T1 in formula (I), and Q represents a hydroxy group or an amino group according to the homologisation sequence chosen, which compounds of formulae (VII/a) and (VII/b), when one of the substituents A represents a halogen atom, may be treated:
with bis(tributyltin), in the presence of a palladium catalyst, to yield the corresponding stannyl compound, which is subjected under the same conditions to the action of a halogen compound Hal-W2xe2x80x94(A)p wherein W2, A and p are as defined for formula (I) and Hal represents a halogen atom,
or with an organometal compound such as a vinyl compound, a tin compound or a boronic acid compound, in the presence or absence of a palladium catalyst, or in basic medium, to yield a compound of formula (VII/c): 
xe2x80x83wherein R1, R2, R3, R4, T2, W1, A, p and Q are as defined hereinbefore and T1, B and W2 are as defined for formula (I), the compounds of formulae (VII/a), (VII/b) and (VII/c) constituting the totality of the compounds of formula (VII): 
xe2x80x83wherein R1, R2, R3, R4, T1, T2 and Q are as defined hereinbefore and W has the same meanings as for formula (I), which compound (VII) is subjected:
either, when Q represents a hydroxy group, to a Mitsunobu-type reaction using as reagent a compound of formula (V): 
xe2x80x83wherein R5, R6, Z and n are as defined for formula (I),
or, after conversion of hydroxy into a leaving group, to the action, in basic medium, of a salt of the compound of formula (V) as defined hereinbefore,
or, when Q represents an amino group, to the action of a compound of formula (VI): 
xe2x80x83wherein R5, R6 and Z are as defined for formula (I) and Alk represents a linear or branched (C1-C6)alkyl group, to yield a compound of formula (VIII): 
xe2x80x83wherein R1, R2, R3, R4, R5, R6, T1, T2, W, Z and n are as defined hereinbefore, which is subjected to an oxidative cleavage reaction to yield a compound of formula (I/d): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, Z, T1, T2, W and n are as defined hereinbefore, and the carboxylic acid function of which may be converted into ester, into hydroxamate or into hydroxamic acid to yield a compound of formula (I/e): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, Z, T1, T2, W and n are as defined hereinbefore and Ye, which is other than a hydroxy group, has the same meanings as Y in formula (I), which compounds of formulae (I/d) and (I/e):
are optionally purified according to a conventional purification technique,
are optionally separated into their isomers according to a conventional separation technique,
and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base, it being understood that the oxidative cleavage of the double bond can be carried out at another stage of the process described above, and that the order of the reactions of that process may be modified with the aim of simplifying the process or if there is incompatibility between certain reactions and the substituents present in the molecule.
The process for the preparation of the compounds of formula (I) wherein R10 represents a hydrogen atom and X represents a xe2x80x94COxe2x80x94Oxe2x80x94 group is characterised in that there is used as starting material a compound of formula (IX): 
wherein R1, R2, R3, R4 are as defined for formula (I), P represents an alkoxy, alkenyloxy or benzyloxy group and m is an integer 0 or 1, which, after protection of one of the two hydroxy functions, is subjected to oxidation in the presence of an appropriate alcohol of formula Pxe2x80x2xe2x80x94OH to yield a compound of formula (X/a): 
wherein R1, R2, R3, R4, m and P are as defined hereinbefore and Pxe2x80x2 represents an alkyl, alkenyl or benzyl group (so selected that the two ester functions present are different), which may be subjected to a sequence of reactions conventional in organic chemistry, for the purpose of homologising the carbon chain carrying the hydroxy function, to yield a compound of formula (X/b): 
wherein R1, R2, R3, R4, P and Pxe2x80x2 are as defined hereinbefore and T1xe2x80x2, which is other than a bond or a methylene group, has the same meanings as T1 in formula (I), which compounds (X/a) and (X/b) are subjected:
either to a Mitsunobu-type reaction using as reagent a compound of formula (V): 
xe2x80x83wherein R5, R6, Z and n are as defined for formula (I),
or, after conversion of hydroxy into a leaving group, to the action of a salt of the compounds of formula (V) as defined hereinbefore to yield a compound of formula (XI): 
xe2x80x83wherein R1, R2, R3, R4, R5, R6, P, Pxe2x80x2 and n are as defined hereinbefore and T1 has the same meanings as for formula (I), which, after selective hydrolysis of one of the two ester functions, is subjected to the action of a compound of formula (XII/a):
HOxe2x80x94T2xe2x80x94Wxe2x80x83xe2x80x83(XII/a)
wherein T2 and W are as defined for formula (I), to yield a compound of formula (XIII/a): 
wherein R1, R2, R3, R4, R5, R6, T1, T2, W, n and p are as defined hereinbefore, it being possible for the compound of formula (XII/a) to be replaced, when that is advantageous, by a compound of formula (XII/b):
HOxe2x80x94T2xe2x80x94W1xe2x80x94(A)pxe2x80x83xe2x80x83(XII/b)
wherein T2, W1, A and p are as defined for formula (I), to yield a compound of formula (XIII/b): 
wherein R1, R2, R3, R4, R5, R6, T1, T2, W1, A, p, P and n are as defined hereinbefore, which, when one of the substituents A represents a halogen atom, may be treated:
with bis(tributyltin), in the presence of a palladium catalyst, to yield the corresponding stannyl compound, which is subjected under the same conditions to the action of a halogen compound Hal-W2xe2x80x94(A)p wherein W2, A and p are as defined for formula (I) and Hal represents a halogen atom,
or with an organometal compound such as a vinyl compound, a tin compound or a boronic acid compound, in the presence or absence of a palladium catalyst, or in basic medium, to yield a compound of formula (XIII/c): 
xe2x80x83wherein R1, R2, R3, R4, R5, R6, T1, T2, W1, A, P and p are as defined hereinbefore, and B and W2 are as defined for formula (I), the compounds of formulae (VIII/a), (VIII/b) and (VIII/c) constituting the totality of the compounds of formula (I/f): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, T1, T2, W, P and n are as defined hereinbefore, the ester function of which may be selectively converted into carboxylic acid to yield a compound of formula (I/g): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, T1, T2, W and n are as defined hereinbefore, and the acid function of which may be converted into hydroxamate or into hydroxamic acid to yield a compound of formula (I/h): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, T1, T2, W and n are as defined hereinbefore, and R has the same meanings as for formula (I), which compounds of formulae (I/f), (I/g) and (I/h):
are optionally purified according to a conventional purification technique,
are optionally separated into their isomers according to a conventional separation technique,
and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base, it being understood that the group P present in the various formulae described hereinbefore must be so chosen as to be resistant to the various reagents used and, with that purpose in mind, may be modified at any point during the synthesis, and that the order of the reactions used in the above process may be modified with the aim of simplifying the process or if there is incompatibility between certain reactions and the substituents present in the molecule.
The process for the preparation of the compounds of formula (I) wherein R10 represents a hydroxy group is characterised in that there is used as starting material a compound of formula (XIV/a): 
wherein R1, R2, R3, R4, T1, T2, X, W1, A and p are as defined for formula (I), which, when one of the substituents A represents a halogen atom, may be treated:
with bis(tributyltin), in the presence of a palladium catalyst, to yield the corresponding stannyl compound, which is subjected under the same conditions to the action of a halogen compound Hal-W2xe2x80x94(A)p wherein W2, A and p are as defined for formula (I) and Hal represents a halogen atom,
or with an organometal compound such as a vinyl compound, a tin compound or a boronic acid compound in the presence or absence of a palladium catalyst or in basic medium, to yield a compound of formula (XIV/b): 
xe2x80x83wherein R1, R2, R3, R4, T1, T2, X, A, B, W1, W2 and p are as defined for formula (I), which compounds (XIV/a) and (XIV/b) are subjected:
either to a Mitsunobu-type reaction using as reagent a compound of formula (V): 
xe2x80x83wherein R5, R6, Z and n are as defined for formula (I),
or, after conversion of hydroxy into a leaving group, to the action of a salt of the compounds of formula (V) as defined hereinbefore, to yield a compound of formula (XV): 
xe2x80x83wherein R1, R2, R3, R4, R1, R6, X, Z, W, T1, T2 and n are as defined for formula (I), which is subjected to a dihydroxylation reaction to yield a compound of formula (XVI): 
xe2x80x83wherein R1, R2, R3, R4, R5, R6, X, Z, W, T1, T2 and n are as defined hereinbefore, the primary alcohol function of which is oxidised, directly or by way of an aldehyde, to yield the corresponding acid of formula (I/i): 
xe2x80x83a particular case of the compounds of formula (I) wherein R1, R2, R3, R4, R5, R6, X, Z, W, T1, T2 and n are as defined hereinbefore, the acid function of which compound (I/i) may be converted into hydroxamate, into hydroxamic acid or into ester to yield a compound of formula (I/j): 
xe2x80x83wherein R1, R2, R3, R4, R5, R6, X, Z, W, T1, T2 and n are as defined for formula (I): and Yj, which is other than a hydroxy group, has the same meanings as Y in formula (I), which compounds of formulae (I/i) and (I/j):
are optionally purified according to a conventional purification technique,
are optionally separated into their isomers according to a conventional separation technique,
and are converted, if desired, into addition salts with a pharmaceutically acceptable acid or base, it being understood that the order of the reactions used in the above process may be modified with the aim of simplifying the process or if there is incompatibility between certain reactions and the substituents present in the molecule.
In the case where, in the compounds of formula (I) it is desired to obtain, R1 and R3 form together with the carbon atoms carrying them a (C5-C8)cycloalkyl group, the processes described above result in xe2x80x9ctrans-transxe2x80x9d (Dtt) and xe2x80x9ctrans-cisxe2x80x9d (Dtc) diastereoisomers: 
wherein X, Y and T1 are as defined for formula (I) and Q is an integer 2, 3, 4 or 5.
The pairs of diastereoisomers are separated by conventional methods at the opportune moment during the process to yield each of them in racemic form.
Among the conventional homologisation sequences used in the above processes there may be mentioned, for example:
conversion of the hydroxy function into a leaving group or activation of that function by a Mitsunobu-type mechanism, replacement by a cyanide, and reduction of the cyano function to amine or hydroxy,
oxidation of the hydroxy function to the aldehyde and increasing the length of the carbon chain by a Wittig or related reaction.
The invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more inert, non-toxic excipients or carriers.
Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral or nasal administration, tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels etc.
The useful dosage varies in accordance with the age and weight of the patient, the nature and severity of the disorder and the administration route, which may be nasal, rectal, parenteral or oral. Generally, the unit dosage ranges from 50 mg to 5 g for a treatment of from 1 to 3 administrations per 24 hours.
The following Examples illustrate the invention but do not limit it in any way. The structures of the described compounds were confirmed by conventional spectroscopic techniques.
The preparations described below result in the starting materials used in the synthesis of the compounds of the invention.
A mixture of (26.4 g; 0.204 mol) of 2,5-dimethoxytetrahydrofuran and 200 ml of a 0.5M hydrochloric acid solution is stirred for 2 hours 30 minutes at 80xc2x0 C. After cooling, the reaction mixture is neutralised with a saturated aqueous solution of KHCO3. An aqueous solution of 0.05 molar equivalents of K2CO3 (15 ml) and then, dropwise, (dimethoxyphosphoryl)acetic acid tert-butyl ester (40.4 ml; 0.204 mol) are added. Finally, 2 molar equivalents of K2CO3 (56.39 g; 0.408 mol) in aqueous solution (100 ml) are added. The whole is stirred at ambient temperature for one night. The residue is extracted with ether, and the organic phase is washed with a saturated aqueous solution of sodium chloride until neutral and dried over magnesium sulphate. After filtration, the filtrate is concentrated to yield the expected compound.
Step a: Benzyl exo-2-oxobicylo[2.2.1]heptane-7-carboxylate
0.25 mol (48 g) of EDC is added to a solution of 0.23 mol (35 g) of exo-2-oxo-bicylo[2.2.1]heptane-7-carboxylic acid (prepared in accordance with the method described in Tetrahedron, 1981, 37, Suppl., 411) in 400 ml of dichloromethane placed at 0xc2x0 C. When the solution has become homogeneous, 0.25 mol (26 ml) of benzyl alcohol is added dropwise followed by 0.022 mol (2.7 g) of DMPA. The reaction mixture is then stirred for 2 hours at ambient temperature, hydrolysed cold with an aqueous 10% hydrochloric acid solution and extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride until neutral and dried over magnesium sulphate. After concentration, the expected product is isolated following purification by chromatography on silica gel using an 8:2 heptane/ethyl acetate mixture as eluant.
Step b: Benzyl 2-trifluoromethanesulphonyloxybicyclo[2.2.1]hept-2-ene-7-carboxylate
150 mmol (31 g) of 2,6-di-tert-butyl-4-methylpyridine and then, dropwise, 150 mmol (25.38 ml) of triflic anhydride, are added to a solution of 137 mmol (33.5 g) of the compound obtained in the preceding Step in 1 litre of dichloromethane. After the addition, the reaction mixture is heated at reflux for 18 hours. A saturated aqueous solution of ammonium chloride is then added (200 ml) and the product is extracted several times with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium chloride until neutral and dried over magnesium sulphate. The expected product is obtained after removal of the solvent by evaporation, and purification by chromatography on silica gel using a 95:5 heptane/ethyl acetate mixture as eluant.
Step c: Benzyl bicyclo[2.2.1]hept-2-ene-7-carboxylate
There are added in succession to a solution of 0.133 mol (50 g) of the compound obtained in the preceding Step, in 650 ml of anhydrous dimethylformamide, 0.4 mol (95 ml) of tributylamine, 2.65 mmol (2 g) of Pd(OAc)2(PPh3)2 and, dropwise, 0.265 mol (10 ml) of formic acid. When the addition is complete, the reaction mixture is heated at 60xc2x0 C. for 2 hours. After concentration, the residue is taken up in ethyl acetate, washed with a saturated aqueous solution of NaHCO3, and then with a saturated aqueous solution of sodium chloride until neutral, and dried over magnesium sulphate. The expected product is obtained after removal of the solvent by evaporation, and purification by chromatography on silica gel using a 95:5 heptane/ether mixture as eluant.
Step d: Benzyl(1R,2R,3S)- and (1S,2S,3R)-2,5-di-(formyl)-1-cyclopentane-carboxylate
A solution, cooled to xe2x88x9278xc2x0 C., of 0.175 mol (40 g) of the compound obtained in the preceding Step in 700 ml of dichloromethane is treated directly with ozone for 2 hours at that temperature. When the starting material has disappeared completely, the reaction mixture is purged with oxygen and then with nitrogen until the blue colour has completely disappeared, and 0.88 mol (64.3 ml) of dimethyl sulphide is added. The mixture is stirred for 24 hours, while allowing a progressive return to ambient temperature. After concentration, the expected product is isolated and can be used directly in the following Step.
Step e: Benzyl(1R,2R,3S)- and (1S,2S,3R)-2,5-bis-(hydroxymethyl)-1-cyclopentanecarboxylate
1.05 mol (148 ml) of 3-ethyl-3-pentanol is added dropwise to a suspension of 0.35 mol (13.3 g) of lithium aluminium hydride in 450 ml of anhydrous tetrahydrofuran placed under argon, and the whole is heated at gentle reflux for 2 hours. After cooling to ambient temperature, the reaction mixture is transferred into a solution of 0.175 mol (45.5 g) of the compound obtained in the preceding Step in 350 ml of anhydrous tetrahydrofuran that has been placed under argon at xe2x88x9278xc2x0 C., and stirring of the mixture is continued at that temperature for 4 hours. The reaction mixture is then hydrolysed by adding 1 litre of a 1M hydrochloric acid solution, with stirring, over a period of 1 hour, while allowing a progressive return to ambient temperature. After extraction with ethyl acetate, washing the organic phase with a saturated aqueous solution of sodium chloride until neutral and drying over magnesium sulphate, the aqueous phase is concentrated. The expected product is isolated by purification by chromatography on silica gel using a 75:25 dichloromethane/-ethyl acetate mixture as eluant.
Step a: trans-1-Bromo-4-[4-chloro-2-butenyl)oxy]benzene
80 mmol (17.4 g) of caesium carbonate are added to a solution, cooled to 0xc2x0 C., of 80 mmol (10 g) of trans-1,4-dichloro-2-butene and 53.3 mmol (9.23 g) of para-bromophenol in 500 ml of acetonitrile, and then the mixture is stirred at ambient temperature for 4 days. The mixture is hydrolysed with 250 ml of a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate. The organic phases are combined and washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate. After evaporation, the expected product is obtained following purification by chromatography on silica gel using a 98:2 petroleum ether/ethyl acetate mixture as eluant.
Step b: 4-(4-Bromophenoxy)-2-butenyl acetate
The compound obtained in the preceding Step (11.5 mmol, 3 g) is dissolved in 150 ml of acetone. After the addition of 13.8 mmol (4.15 g) of tetrabutylammonium acetate, the mixture is heated at reflux for 5 hours. The solvent is evaporated off and then the residue is redissolved in 250 ml of dichloromethane. The solution is washed with water (3xc3x97100 ml), dried over magnesium sulphate and concentrated. The oily residue is purified by chromatography on silica gel, using a 97:3 petroleum ether/ethyl acetate mixture as eluant, to yield the expected compound.
Step c: 4-(4-Bromophenoxy)-2-buten-1-ol
54 ml of a 2M aqueous sodium hydroxide solution are added to a solution of 10.9 mmol (3.1 g) of the compound obtained in the preceding Step in 50 ml of methanol. The mixture is stirred at ambient temperature for 16 hours and then neutralised with a 1M aqueous hydrochloric acid solution. The aqueous phase is extracted with dichloromethane (3xc3x97100 ml). The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on silica gel, using an 8:2 petroleum ether/ethyl acetate mixture as eluant, to yield the expected product.
Step d: Ethyl 3-[(4-bromophenoxy)methyl]-4-pentenoate
A mixture of 61.7 mmol (11.3 ml) of triethyl orthoacetate, 0.05 mmol (4 xcexcl) of propionic acid and 10.3 mmol (2.5 g) of the compound described in the preceding Step is heated at 125xc2x0 C. for a whole day while distilling off the ethanol formed. The temperature is subsequently brought to 135xc2x0 C. for 1 night and then triethyl orthoacetate is distilled off in vacuo. The desired product is obtained by purification by chromatography on silica gel using a 98:2 petroleum ether/ethyl acetate mixture as eluant.
Step e: 3-[(4-Bromophenoxy)methyl]-4-penten-1-ol
5.32 mmol (0.2 g) of lithium aluminium hydride suspended in 10 ml of diethyl ether are slowly added to a solution, cooled to xe2x88x9278xc2x0 C., of 6.64 mmol (2.1 g) of the compound obtained in the preceding Step in 25 ml of anhydrous diethyl ether, and the mixture is then stirred for 24 hours at xe2x88x9278xc2x0 C. The reaction is hydrolysed with water, the phases are separated, and the aqueous phase is extracted 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate. Removal of the solvent by evaporation yields the expected product.
Step a: 2-[2-(Methoxycarbonyl)ethyl]acrylic acid
120 g of Amberlyst-15 resin are added to a solution of itaconic acid, 0.76 mole (100 g), in 1.5 litres of anhydrous methanol. The whole is stirred slowly for 48 hours at ambient temperature. The reaction mixture is then filtered. The methyl monoester is thus obtained by simple concentration of the filtrate.
Step b: Methyl 3-tert-butoxycarbonyl-3-butenoate
To a solution, cooled to 0xc2x0 C., of methyl monoester (0.18 mol, 26 g) obtained in Step a in 130 ml of anhydrous CH2Cl2, there is added in the course of 1 hour isobutylene, and then 1.3 ml of concentrated sulphuric acid. The whole, hermetically sealed, is stirred at ambient temperature for 24 hours. The reaction mixture is then neutralised cold with a saturated NaHCO3 solution and subsequently extracted with CH2Cl2. The organic phase is then washed with a saturated NaCl solution until neutral and subsequently dried over MgSO4. The diester is obtained in the form of a colourless oil by concentrating the solvent to dryness.
Step c: 3-tert-Butoxycarbonyl-3-butenoic acid
A solution of 0.26 mole (10.78 g) of lithium hydroxide in 100 ml of H2O is added to 0.17 mol (34.3 g) of the diester compound obtained in Step b dissolved in 100 ml of dioxane. The whole is stirred at ambient temperature for 24 hours. 100 ml of H2O are then added and the aqueous phase is washed twice with 100 ml of Et2O each time, then acidified with dilute HCl and, finally, extracted with AcOEt. The organic phase is subsequently washed with a saturated NaCl solution and then dried over MgSO4. The product is obtained in the form of a colourless oil by concentrating the solvent to dryness.
Step d: tert-Butyl 4-hydroxy-2-methylenebutyrate
A solution of the compound described in the preceding Step (4.85 mmol, 0.9 g) in 10 ml of THF is added dropwise to a suspension of 5.82 mmol (0.22 g) of NaBH4 in 20 ml of anhydrous THF, and the whole is stirred at ambient temperature for 1 hour. It is brought to 0xc2x0 C. and then a solution of I2 (2.42 mmol, 0.615 g) in 20 ml of THF is added and the reaction mixture is subsequently stirred at ambient temperature for 24 hours. The mixture is hydrolysed with a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is then washed with a saturated sodium chloride solution, dried over magnesium sulphate and concentrated to yield the expected compound.
Step a: 4-Bromophenethyl thioacetate
5 mmol (1 ml) of DIAD are added to a solution, cooled to 0xc2x0 C., of 5 mmol (1.32 g) of triphenylphosphine in 16 ml of tetrahydrofuran. After stirring the mixture cold for 15 minutes, there is added dropwise thereto a mixture of 2.5 mmol (0.5 g) of 2-(4-bromophenyl)-1-ethanol and 5 mmol (0.83 ml) of thioacetic acid diluted with 5 ml of tetrahydrofuran. The mixture is stirred cold for a further 10 minutes and then the temperature is brought to ambient temperature for 18 hours. The solvents are evaporated off. The residue is taken up in diisopropyl ether and the precipitate formed is filtered off. The filtrate is concentrated and then purified by chromatography on silica gel. using petroleum ether as eluant, to yield the expected product.
Step b: 2-(4-Bromophenyl)-1-ethanethiol
7.48 mmol (0.284 mg) of lithium aluminium hydride dissolved in 21 ml of diethyl ether are added dropwise to a solution, cooled to 0xc2x0 C. by an ice bath, of 1.87 mmol (0.48 g) of the compound described in the preceding Step in 13 ml of diethyl ether. After stirring cold for 2 hours, the mixture is hydrolysed with an aqueous N hydrochloric acid solution (13 ml). The mixture is extracted with diethyl ether (twice with 250 ml each time). The ethereal phases are washed with water (twice with 100 ml each time) and then dried over magnesium sulphate before being concentrated. Purification by chromatography on silica gel, using a 95:5 petroleum ether/diethyl ether mixture as eluant, yields the expected product.
The expected product is obtained in accordance with the procedure described in Preparation E, with the replacement of 2-(4-bromophenyl)-1-ethanol with (4-bromophenyl)methanol in Step a.
The expected product is obtained in accordance with the procedure described in Preparation C, with the replacement of para-bromophenol with 2-(4-bromophenyl)ethanol in Step a.
The expected product is obtained in accordance with the procedure described in Preparation C, using 3-chloromethyl-3-chloro-1-propene as starting material in Step a.